Abstract
Ethyl rosmarinate (RAE) is one of the active constituents from Clinopodium chinense (Benth.) O. Kuntze, which is used for diabetic treatment in Chinese folk medicine. In this study, we investigated the protective effect of RAE on high glucose-induced injury in endothelial cells and explored its underlying mechanisms. Our results showed that both RAE and rosmarinic acid (RA) increased cell viability, decreased the production of reactive oxygen species (ROS), and attenuated high glucose-induced endothelial cells apoptosis in a dose-dependent manner, as evidenced by Hochest staining, Annexin V–FITC/PI double staining, and caspase-3 activity. RAE and RA both elevated Bcl-2 expression and reduced Bax expression, according to Western blot. We also found that LY294002 (phosphatidylinositol 3-kinase, or PI3K inhibitor) weakened the protective effect of RAE. In addition, PDTC (nuclear factor-κB, or NF-κB inhibitor) and SP600125 (c-Jun N-terminal kinase, or JNK inhibitor) could inhibit the apoptosis in endothelial cells caused by high glucose. Further, we demonstrated that RAE activated Akt, and the molecular docking analysis predicted that RAE showed more affinity with Akt than RA. Moreover, we found that RAE inhibited the activation of NF-κB and JNK. These results suggested that RAE protected endothelial cells from high glucose-induced apoptosis by alleviating reactive oxygen species (ROS) generation, and regulating the PI3K/Akt/Bcl-2 pathway, the NF-κB pathway, and the JNK pathway. In general, RAE showed greater potency than RA equivalent.
Highlights
Diabetes is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period [1], which can cause many complications including cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the eyes, etc. [2]
We examined the protective effects of RAE and rosmarinic acid (RA) on reactive oxygen species (ROS) generation and apoptosis in vascular endothelial cells exposed to high glucose
We found that the protect effect of RAE on endothelial cells apoptosis induced by high glucose was better than RA at the concentration of 10 μM
Summary
Diabetes is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period [1], which can cause many complications including cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the eyes, etc. [2]. The JNK pathway is involved in the regulation of endothelial cells apoptosis in response to high glucose [9]. Previous studies have shown that hyperglycemia enhances free radical production and induces oxidative damage, which in its turn activates the cell death pathways associated with apoptosis and necrosis [12,13]. Exploring the relationship between drugs and these pathways involved with high glucose-induced apoptosis and finding potential drug targets may contribute to develop new agents of anti-diabetic vascular complications. CC was proved to be cytoprotective on vascular endothelial cells induced by high glucose in our previous study [15]. We examined the protective effects of RAE and RA on ROS generation and apoptosis in vascular endothelial cells exposed to high glucose. We detected the expression of apoptotic pathway-involved proteins including Akt, NF-κB, and JNK to explore the underlying molecular mechanisms of RAE
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